Role of the activating mutation Val617Phe of Janus kinase 2 gene in myeloproliferative diseases and significance of its detection

2007 ◽  
Vol 148 (5) ◽  
pp. 203-210 ◽  
Author(s):  
Hajnalka Andrikovics ◽  
Anikó Szilvási ◽  
Nóra Meggyesi ◽  
Viktória Király ◽  
Gabriella Halm ◽  
...  
Keyword(s):  
Unknown Origin ◽  
Janus Kinase ◽  
Polycythaemia Vera ◽  
Essential Thrombocythaemia ◽  
Janus Kinase 2 ◽  
Idiopathic Myelofibrosis ◽  
Cell Counts ◽  
Myeloproliferative Syndrome ◽  
Activating Mutation

The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoetic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythaemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycytaemia vera, 56,6% (56/99) in essential thrombocythaemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythaemia vera and essential thrombocythaemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Althought the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of unknown origin.

scholarly journals The Role of JAK2 in Myeloproliferative Diseases Diagnosis

2018 ◽  
Vol 1 (2) ◽  
pp. 135
Author(s):  
Yudith Annisa Ayu Rezkitha ◽  
S. Ugroseno Yudho Bintoro ◽  
Ami Ashariati
Keyword(s):  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Polycythaemia Vera ◽  
Janus Kinase 2 ◽  
Myeloproliferative Diseases ◽  
Diagnosis Criteria ◽  
Transduction Signal ◽  
Essential Thrombocytemia

Janus Kinase 2 (JAK2) plays an important role in mediating transduction signal of hematopoiesis, including in the pathogenesis of Myeloproliferative diseases (MPD). Various studies have been carried out to identify the position of aleles in tyrosine encoding mutations. Although the effect of JAK2 mutations is still not fully understood, the discovery of these mutations might be able to differentiate the types of polycythaemia vera, essential thrombocytemia, and primary myelofibrosis with malignant abnormalities. WHO has revised the MPD diagnosis criteria following this finding. This review will discuss the role of JAK2.

Direct Activation of STAT5 by TEL-Lyn Fusion Protein Promotes Induction of Myeloproliferative Neoplasms with Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4114-4114
Author(s):  
Yusuke Takeda ◽  
Chiaki Nakaseko ◽  
Hiroaki Tanaka ◽  
Masahiro Takeuchi ◽  
Makiko Yui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Signaling Molecules ◽  
Janus Kinase ◽  
Idiopathic Myelofibrosis ◽  
Lyn Kinase

Abstract Abstract 4114 Background Myeloproliferative neoplasms (MPN), a group of hematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. The V617F somatic mutation in the Janus kinase 2 (JAK2) gene has recently been found in the majority of patients with polycythemia vera (PV) and more than half of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). The expression of JAK2 V617F causes a PV-like disease with myelofibrosis in a murine bone marrow (BM) transplant model. In addition, a gain-of-function c-MPL W515 mutation was described in nearly 10% of patients with JAK2 V617F-negative IMF. However, the mechanism responsible for MPD and the formation of myelofibrosis in patients without JAK2 or c-MPL mutations is still unclear. We previously identified the fusion of the TEL gene to the Lyn gene (TEL-Lyn) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of TEL-Lyn into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged Lyn kinase in the pathogenesis of MPN with myelofibrosis. However, the signaling molecules directly downstream from and activated by TEL-Lyn remain unknown. Design and Methods We examined the signaling pathways activated by TEL-Lyn by Western blotting, immunoprecipitation, and in vitro kinase assay using a TEL-Lyn kinase-dead mutant as a control. We further characterized the functional properties of Stat5-deficient HSCs transduced with TEL-Lyn by colony-forming assay and bone marrow transplantation to evaluate the role of STAT5 in TEL-Lyn-induced MPN. Results TEL-Lyn was demonstrated to be constitutively active as a kinase through autophosphorylation. In TEL-Lyn-expressing cells, STAT5, STAT3, and Akt were constitutively activated. Among these signaling molecules, STAT5 was activated most prominently and this occurred without the activation of Jak2, the major kinase for STAT5. TEL-Lyn was co-immunoprecipitated with STAT5, and STAT5 was phosphorylated when incubated with TEL-Lyn, but not with TEL-Lyn kinase-dead mutant. These results indicate that TEL-Lyn interacts with STAT5 and directly activates STAT5 both in vitro and in vivo. Of note, the capacity of TEL-Lyn to support the formation of hematopoietic colonies under cytokine-free conditions in vitro and to induce MPN with myelofibrosis in vivo was profoundly attenuated in a Stat5-null background. Conclusions In this study, we clearly showed that TEL-Lyn directly activates STAT5 and the capacity of TEL-Lyn to induce MPN with myelofibrosis was profoundly attenuated in the absence of STAT5. Our findings of TEL-Lyn in this study support the role of the Src family kinases in the regulation of STAT pathways and implicate active Lyn in the alternative pathway for STAT activation in pathological cytokine signaling. Our mouse model of MPD with myelofibrosis would be beneficial for the analysis of therapeutic approaches for myelofibrosis. Disclosures: No relevant conflicts of interest to declare.

Atypical haematological presentation in a case of polycythaemia vera with a new variant mutation detected in exon 12: c.1605G>T (p.Met535Ile)

2017 ◽  
Vol 71 (2) ◽  
pp. 180-184 ◽  
Author(s):  
Amélia Soraia Andrade Pita ◽  
Ana Paula da Silva Azevedo ◽  
Alice Reichert ◽  
Cândido José Pimenta da Silva ◽  
Vanessa Henriques ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Novel Mutation ◽  
Janus Kinase ◽  
Polycythaemia Vera ◽  
Janus Kinase 2 ◽  
Gain Of Function ◽  
New Variant

One of the major genetic insights into the pathogenesis of polycythaemia vera included the identification of the somatic point gain-of-function mutations in Janus kinase 2 gene—first JAK2V617F on exon 14, present in 95%–97% of the cases, and later on exon 12. In the literature, we can find some reported studies where different exon 12 mutations are identified. Unlike patients with JAK2V617F mutation in exon 14, the mutation at exon 12 is not usually associated with an increase in the three haematopoietic series (erythrocytosis, leucocytosis and thrombocytosis). It appears to be associated with a distinct syndrome, mostly characterised by isolated and more marked erythrocytosis, independently of the mutational variant. We report here the case of a patient who is JAK2exon 12 positive, presenting a novel mutation—c.1605G>T (p.Met535Ile)—associated with c.1612C>T (p.His538Tyr) mutation previously described, evidencing an atypical clinical phenotype.

Role of a Janus kinase 2-dependent signaling pathway in platelet activation

2014 ◽  
Vol 133 (6) ◽  
pp. 1088-1096 ◽  
Author(s):  
Wan-Jung Lu ◽  
Kao-Chang Lin ◽  
Shih-Yi Huang ◽  
Philip Aloysius Thomas ◽  
Yu-Hua Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Platelet Activation ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Dependent Signaling Pathway

The role of Janus kinase 2 (JAK2) activation in pneumococcal EstA protein-induced inflammatory response in RAW 264.7 macrophages

2011 ◽  
Vol 51 (4) ◽  
pp. 297-303 ◽  
Author(s):  
Elias Gebru ◽  
Eun-Hee Kang ◽  
Dereje Damte ◽  
Joong-Su Lee ◽  
Seung-Hee Jang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Janus Kinase ◽  
Raw 264.7 ◽  
Janus Kinase 2 ◽  
Raw 264.7 Macrophages

Chronic idiopathic myelofibrosis (CIMF) resulting from a unique 3;9 translocation disrupting the janus kinase 2 (JAK2) gene

2006 ◽  
Vol 81 (3) ◽  
pp. 217-223 ◽  
Author(s):  
Hon Fong L. Mark ◽  
Edgar A. Sotomayor ◽  
Marilu Nelson ◽  
Fernando Chaves ◽  
Warren G. Sanger ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Idiopathic Myelofibrosis ◽  
Chronic Idiopathic Myelofibrosis

Idiopathic myelofibrosis and pyoderma gangrenosum involving a mutation of Janus kinase 2 (JAK2V617F), showing poor prognosis

2013 ◽  
Vol 23 (2) ◽  
pp. 256-257 ◽  
Author(s):  
Maejima Hideki ◽  
Takano Tetsurou ◽  
Funatsu Sakae ◽  
Katsuoka Kensei ◽  
Oobe Makoto ◽  
...  
Keyword(s):  
Pyoderma Gangrenosum ◽  
Poor Prognosis ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Idiopathic Myelofibrosis

scholarly journals Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1394 ◽  
Author(s):  
Mi-Ae Kang ◽  
Jongsung Lee ◽  
Sang Ha ◽  
Chang Lee ◽  
Kyoung Kim ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Proliferation Rate ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Forkhead Box ◽  
Cell Proliferation Rate

Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients.

scholarly journals PRL-Induced ERα Gene Expression Is Mediated by Janus Kinase 2 (Jak2) While Signal Transducer and Activator of Transcription 5b (Stat5b) Phosphorylation Involves Jak2 and a Second Tyrosine Kinase

2001 ◽  
Vol 15 (11) ◽  
pp. 1941-1952
Author(s):  
Jonna Frasor ◽  
Uriel Barkai ◽  
Liping Zhong ◽  
Asgerally T. Fazleabas ◽  
Geula Gibori
Keyword(s):  
Tyrosine Kinase ◽  
Promoter Activity ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Mrna Levels ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Cos Cells ◽  
Stimulation Of

Abstract In the rat corpus luteum of pregnancy, PRL stimulation of ER expression is a prerequisite for E2 to have any luteotropic effect. Previous work from our laboratory has established that PRL stimulates ERα expression at the level of transcription and that the transcription factor Stat5 (signal transducer and activator of transcription 5) mediates this stimulation. Since it is well established that PRL activates Stat5 through the tyrosine kinase, Janus kinase 2 (Jak2), the role of Jak2 in PRL regulation of ERα expression was investigated. In primary luteinized granulosa cells, the general tyrosine kinase inhibitors, genistein and AG18, and the Jak2 inhibitor, AG490, prevented PRL stimulation of ERα mRNA levels, suggesting that PRL signaling to the ERα gene requires Jak2 activity. However, using an antibody that recognizes the tyrosine-phosphorylated forms of both Stat5a and Stat5b (Y694/Y699), it was found that AG490 could inhibit PRL-induced Stat5a phosphorylation only and had little or no effect on Stat5b phosphorylation. These effects of AG490 were confirmed in COS cells overexpressing Stat5b. Also in COS cells, a kinase-negative Jak2 prevented PRL stimulation of ERα promoter activity and Stat5b phosphorylation while a constitutively active Jak2 could stimulate both in the absence of PRL. Furthermore, kinase-negative-Jak2, but not AG490, could inhibit Stat5b nuclear translocation and DNA binding. Therefore, it seems that in the presence of AG490, Stat5b remains phosphorylated, is located in the nucleus and capable of binding DNA, but is apparently transcriptionally inactive. These findings suggest that PRL may activate a second tyrosine kinase, other than Jak2, that is capable of phosphorylating Stat5b without inducing transcriptional activity. To investigate whether another signaling pathway is involved, the src kinase inhibitor PP2 and the phosphoinositol-3 kinase inhibitor (PI3K), LY294002, were used. Neither inhibitor alone had any major effect on PRL regulation of ERα promoter activity or on PRL-induced Stat5b phosphorylation. However, the combination of AG490 and LY294002 largely prevented PRL-induced Stat5b phosphorylation. These findings indicate that PRL stimulation of ERα expression requires Jak2 and also that PRL can induce Stat5b phosphorylation through two tyrosine kinases, Jak2 and one downstream of PI3K. Furthermore, these results suggest that the role of Jak2 in activating Stat5b may be through a mechanism other than simply inducing Stat5b phosphorylation.

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